This project is a study, by means of electron microscopy and other morphologic techniques, of the permeability of capillaries to large molecules. The basic technique used in the study is to introduce tracer molecules that can be detected by electron microscopy into the circulation and then follow their passage through the capillary wall into the pericapillary space. We use principally two tracers, horseradish peroxidase and ferritin, for this purpose. Because individual ferritin molecules can be recognized by electron microscopy, quantitative studies can be carried out with this tracer. We are studying the permeability of two structural different types of capillaries: the continuous capillary of muscle and the fenestrated capillaries of the intestine. We are assessing the role of micropinocytic vesicles, fenestrae bridged by thin membranes and junctions of endothelial cells as pathways for transfer of large molecules. In our studies we have observed that following IV injection peroxidase escapes more rapidly from venules than from capillaries. We shall try to substantiate this observation quantitatively with ferritin and see whether we can detect the morphologic basis for the difference. We shall initiate a series of studies to determine how lymphatics of the diaphragm take up protein tracers from the surrounding interstitium. We have been attempting to analyze the structure of endothelial junctions in three dimensions by freeze-fracture. One worker in the laboratory is carrying out a combined ultrastructural and physiologic analysis of the chemoreceptor function of the carotid body. Another is studying small, intensely fluorescent cells in the nodose ganglion.